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Khare S, Jog R, Bright A, Burgess DJ, Chakder SK, Gokulan K. Evaluation of mucosal immune profile associated with Zileuton nanocrystal-formulated BCS-II drug upon oral administration in Sprague Dawley rats. Nanotoxicology 2023; 17:583-603. [PMID: 38146991 DOI: 10.1080/17435390.2023.2289940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 10/23/2023] [Accepted: 11/23/2023] [Indexed: 12/27/2023]
Abstract
Nanocrystal drug formulation involves several critical manufacturing procedures that result in complex structures to improve drug solubility, dissolution, bioavailability, and consequently the efficacy of poorly soluble Biopharmaceutics Classification System (BCS) II and IV drugs. Nanocrystal formulation of an already approved oral drug may need additional immunotoxic assessment due to changes in the physical properties of the active pharmaceutical ingredient (API). In this study, we selected Zileuton, an FDA-approved drug that belongs to BCS-II for nanocrystal formulation. To evaluate the efficacy and mucosal immune profile of the nanocrystal drug, 10-week-old rats were dosed using capsules containing either API alone or nanocrystal formulated Zileuton (NDZ), or with a physical mixture (PM) using flexible oral gavage syringes. Control groups consisted of untreated, or placebo treated animals. Test formulations were administrated to rats at a dose of 30 mg/kg body weight (bw) once a day for 15 days. The rats treated with NDZ or PM had approximately 4.0 times lower (7.5 mg/kg bw) API when compared to the micron sized API treated rats. At the end of treatment, mucosal (intestinal tissue) and circulating cytokines were measured. The immunological response revealed that NDZ decreased several proinflammatory cytokines in the ileal mucosa (Interleukin-18, Tumor necrosis Factor-α and RANTES [regulated upon activation, normal T cell expressed and secreted]). A similar pattern in the cytokine profile was also observed for the micron sized API and PM treated rats. The cytokine production revealed that there was a significant increase in the production of IL-1β and IL-10 in the females in all experimental groups. Additionally, NDZ showed an immunosuppressive effect on proinflammatory cytokines both locally and systemically, which was similar to the response in micron sized API treated rats. These findings indicate that NDZ significantly decreased several proinflammatory cytokines and it displays less immunotoxicity, probably due to the nanocrystal formulation. Thus, the nanocrystal formulation is more suitable for oral drug delivery, as it exhibited better efficacy, safety, and reduced toxicity.
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Affiliation(s)
- Sangeeta Khare
- Division of Microbiology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR, USA
| | - Rajan Jog
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, USA
| | - Anshel Bright
- Division of Microbiology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR, USA
| | - Diane J Burgess
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, USA
| | - Sushanta K Chakder
- Center for Drug Evaluation Research, US Food and Drug Administration, Silver Spring, MD, USA
| | - Kuppan Gokulan
- Division of Microbiology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR, USA
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Macharia JM, Varjas T, Mwangi RW, Káposztás Z, Rozmann N, Pintér M, Wagara IN, Raposa BL. Modulatory Properties of Aloe secundiflora's Methanolic Extracts on Targeted Genes in Colorectal Cancer Management. Cancers (Basel) 2023; 15:5002. [PMID: 37894369 PMCID: PMC10605537 DOI: 10.3390/cancers15205002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 10/08/2023] [Accepted: 10/12/2023] [Indexed: 10/29/2023] Open
Abstract
Colon tumors have a very complicated and poorly understood pathogenesis. Plant-based organic compounds might provide a novel source for cancer treatment with a sufficient novel mode of action. The objective of this study was to analyze and evaluate the efficacy of Aloe secundiflora's (AS) methanolic extracts on the expression of CASPS9, 5-LOX, Bcl2, Bcl-xL, and COX-2 in colorectal cancer (CRC) management. Caco-2 cell lines were used in the experimental study. In the serial exhaustive extraction (SEE) method, methanol was utilized as the extraction solvent. Upon treatment of CASPS9 with the methanolic extracts, the expression of the genes was progressively upregulated, thus, dose-dependently increasing the rate of apoptosis. On the other hand, the expressions of 5-LOX, Bcl2, and Bcl-xL were variably downregulated in a dose-dependent manner. This is a unique novel study that evaluated the effects of AS methanolic extracts in vitro on CRC cell lines using different dosage concentrations. We, therefore, recommend the utilization of AS and the application of methanol as the extraction solvent of choice for maximum modulatory benefits in CRC management. In addition, we suggest research on the specific metabolites in AS involved in the modulatory pathways that suppress the development of CRC and potential metastases.
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Affiliation(s)
- John M. Macharia
- Doctoral School of Health Sciences, Faculty of Health Science, University of Pẻcs, 7621 Pẻcs, Hungary
| | - Timea Varjas
- Department of Public Health Medicine, Medical School, University of Pẻcs, 7621 Pẻcs, Hungary
| | - Ruth W. Mwangi
- Department of Vegetable and Mushroom Growing, Hungarian University of Agriculture and Life Sciences, 1118 Budapest, Hungary
- Department of Biological Sciences, Egerton University, Nakuru P.O. Box 3366-20100, Kenya
| | - Zsolt Káposztás
- Faculty of Health Sciences, University of Pécs, 7621 Pécs, Hungary (B.L.R.)
| | - Nóra Rozmann
- Doctoral School of Health Sciences, Faculty of Health Science, University of Pẻcs, 7621 Pẻcs, Hungary
| | - Márton Pintér
- Doctoral School of Health Sciences, Faculty of Health Science, University of Pẻcs, 7621 Pẻcs, Hungary
| | - Isabel N. Wagara
- Department of Biological Sciences, Egerton University, Nakuru P.O. Box 3366-20100, Kenya
| | - Bence L. Raposa
- Faculty of Health Sciences, University of Pécs, 7621 Pécs, Hungary (B.L.R.)
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Guo J, Pan Y, Chen J, Jin P, Tang S, Wang H, Su H, Wang Q, Chen C, Xiong F, Liu K, Li Y, Su M, Tang T, He Y, Sheng J. Serum metabolite signatures in normal individuals and patients with colorectal adenoma or colorectal cancer using UPLC-MS/MS method. J Proteomics 2023; 270:104741. [PMID: 36174955 DOI: 10.1016/j.jprot.2022.104741] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 08/19/2022] [Accepted: 09/06/2022] [Indexed: 02/01/2023]
Abstract
Colorectal cancer (CRC) is one of the main causes of cancer-related deaths worldwide. Sporadic CRC develops from normal mucosa via adenoma to adenocarcinoma, which provides a long screening window for clinical detection. However, early diagnosis of sporadic colorectal adenoma (CRA) and CRC using serum metabolic screening remains unclear. The purpose of this study was to identify some promising signatures for distinguishing the different pathological metabolites of colorectal mucosal malignant transformation. A total of 238 endogenous metabolites were elected. We found that CRA and CRC patients had 72 and 73 different metabolites compared with healthy controls, respectively. There were 20 different metabolites between CRA and CRC patients. The potential metabolites of tumor growth (including patients with CRA and CRC) were found, such as A-d-glucose, D-mannose, N-acetyl-D-glucosamine, L-cystine, Sarcosine, TXB 2, 12-Hete, and chenodeoxycholic acid. Compared with CRA, 3,4,5-trimethoxybenzoic acid was significantly higher in CRC patients. There results prompt us to use the potential serum signatures to screen CRC as the novel strategy. Serum metabolite screening is useful for early detection of mucosal intestinal malignancy. We will further investigate the roles of these promising biomarkers during intestinal tumorigenesis in future. SIGNIFICANCE: CRC is one of the main causes of cancer-related deaths worldwide. Sporadic CRC develops from normal mucosa via adenomas to adenocarcinoma, which provides a long screening window for about 5-10 years. We adopt the metabolic analysis of extensive targeted metabolic technology. The main purpose of the metabolic group analysis is to detect and screen the different metabolites, thereby performing related functional prediction and analysis of the differential metabolites. In our study, 30 samples are selected, divided into 3 groups for metabolic analysis, and 238 metabolites are elected. In 238 metabolites, we find that CRA patients have 72 different metabolites compared with health control. Compared with health control, CRC have 73 different metabolites. Compared with CRA and CRC patients, there are 20 different metabolites. The annotation results of the significantly different metabolites are classified according to the KEGG pathway type. The potential metabolites of tumor growth stage (including patients with CRA and CRC) are found, such as A-d-glucose, D-mannose, N-acetyl-D-glucosamine, L-cystine, sarcosine, TXB 2, 12-Hete and chenodeoxycholic acid. Compared with CRA patients, CRC patients had significantly higher 3,4,5-trimethoxybenzoic acid level. It is prompted to use serum different metabolites to screen CRC to provide new possibilities.
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Affiliation(s)
- Jiachi Guo
- Chinese PLA General Hospital, No. 28, Fuxing Road Haidian District, Beijing 100853, China; Department of Gastroenterology, The Seventh Medical Center of Chinese PLA General Hospital, No. 5 Nanmencang, Dongcheng District, Beijing 100700, China
| | - Yuanming Pan
- Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, No. 9 Beiguan Street, Tongzhou District, Beijing 101149, China
| | - Jigui Chen
- Department of Colorectal and Anal Surgery Wuhan, No. 8 Hospital. No. 1307 Zhongshan Avenue, Jiang'an District, Hankou, Wuhan City, Hubei 430010, China
| | - Peng Jin
- Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, No. 28, Fuxing Road Haidian District, Beijing 100853, China; Department of Gastroenterology, The Seventh Medical Center of Chinese PLA General Hospital, No. 5 Nanmencang, Dongcheng District, Beijing 100700, China
| | - Shan Tang
- Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, No. 28, Fuxing Road Haidian District, Beijing 100853, China; Department of Gastroenterology, The Seventh Medical Center of Chinese PLA General Hospital, No. 5 Nanmencang, Dongcheng District, Beijing 100700, China
| | - Haihong Wang
- Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, No. 28, Fuxing Road Haidian District, Beijing 100853, China; Department of Gastroenterology, The Seventh Medical Center of Chinese PLA General Hospital, No. 5 Nanmencang, Dongcheng District, Beijing 100700, China
| | - Hui Su
- Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, No. 28, Fuxing Road Haidian District, Beijing 100853, China; Department of Gastroenterology, The Seventh Medical Center of Chinese PLA General Hospital, No. 5 Nanmencang, Dongcheng District, Beijing 100700, China
| | - Qian Wang
- Department of Colorectal and Anal Surgery Wuhan, No. 8 Hospital. No. 1307 Zhongshan Avenue, Jiang'an District, Hankou, Wuhan City, Hubei 430010, China
| | - Chao Chen
- Department of Colorectal and Anal Surgery Wuhan, No. 8 Hospital. No. 1307 Zhongshan Avenue, Jiang'an District, Hankou, Wuhan City, Hubei 430010, China
| | - Fei Xiong
- Department of Colorectal and Anal Surgery Wuhan, No. 8 Hospital. No. 1307 Zhongshan Avenue, Jiang'an District, Hankou, Wuhan City, Hubei 430010, China
| | - Kejia Liu
- DHC Mediway Technology Co., Ltd., 14F, Zijin Digital Park, Zhongguancun, Haidian District, Beijing 100190, China
| | - Yansheng Li
- DHC Mediway Technology Co., Ltd., 14F, Zijin Digital Park, Zhongguancun, Haidian District, Beijing 100190, China
| | - Mingliang Su
- DHC Mediway Technology Co., Ltd., 14F, Zijin Digital Park, Zhongguancun, Haidian District, Beijing 100190, China
| | - Tang Tang
- Wuhan Metwell Biotechnology Co., Ltd., Building B7/B8, Biological Industry Innovation Base, 666 Gaoxin Avenue, Donghu New Technology Development Zone, Wuhan City, Hubei 430075, China
| | - Yuqi He
- Department of Gastroenterology, The Seventh Medical Center of Chinese PLA General Hospital, No. 5 Nanmencang, Dongcheng District, Beijing 100700, China; The Second School of Clinical Medicine, Southern Medical University, 253 Middle Industrial Avenue, Guangzhou City, Guangdong 510280, China; Department of Gastroenterology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, No. 9 Beiguan Street, Tongzhou District, Beijing 101149, China.
| | - Jianqiu Sheng
- Chinese PLA General Hospital, No. 28, Fuxing Road Haidian District, Beijing 100853, China; Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, No. 28, Fuxing Road Haidian District, Beijing 100853, China; Department of Gastroenterology, The Seventh Medical Center of Chinese PLA General Hospital, No. 5 Nanmencang, Dongcheng District, Beijing 100700, China.
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Mohammed A, Shoemaker RH. Targeting the Leukotriene Pathway for Colon Cancer Interception. Cancer Prev Res (Phila) 2022; 15:637-640. [PMID: 36193659 DOI: 10.1158/1940-6207.capr-22-0331] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 08/01/2022] [Accepted: 08/01/2022] [Indexed: 11/16/2022]
Abstract
The role of chronic inflammation and arachidonic acid (AA) metabolism in tumor progression has been well characterized for variety of cancers, with compelling data for colon cancer. Several preclinical and clinical studies primarily focused on inhibiting the cyclooxygenase pathways using NSAIDs and aspirin for colon cancer prevention. However, emerging evidence clearly supports the pro-tumorigenic role of 5-lipoxygenase and its downstream leukotriene pathway within AA metabolism. As discussed in the current issue, targeting the leukotriene pathway by cysteinyl leukotriene receptor antagonist (LTRA) montelukast suppressed formation of aberrant crypt foci (ACF) and cell proliferation in colonic epithelium, suggesting the potential of LTRAs for colon cancer prevention. Although this is a short clinical chemoprevention trial to explore the effects of LTRAs against ACF development, it is a significant and timely study opening avenues to further explore the possibilities of using LTRAs in other inflammation-associated precancerous lesions as well. In this spotlight commentary, we highlight the implications of their data and the opportunities for developing LTRAs as potential candidates for colorectal cancer interception. See related article by Higurashi et al., p. 661.
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Razdan A, Main NM, Chiu V, Shackel NA, de Souza P, Bryant K, Scott KF. Targeting the eicosanoid pathway in hepatocellular carcinoma. Am J Cancer Res 2021; 11:2456-2476. [PMID: 34249410 PMCID: PMC8263695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 04/06/2021] [Indexed: 06/13/2023] Open
Abstract
Liver cancer has variable incidence worldwide and high mortality. Histologically, the most common subtype of liver cancer is hepatocellular carcinoma (HCC). Approximately 30-40% of HCC patients are diagnosed at an advanced stage, and at present, there are limited treatment options for such patients. The current first-line therapy with tyrosine kinase inhibitors, sorafenib or lenvatinib, prolongs survival by a median of about 2.5-3 months after which the disease normally progresses. Additionally, many patients discontinue the use of tyrosine kinase inhibitors due to toxicity or may not be suitable candidates due to co-morbidity or frailty. It is, therefore, imperative to identify novel therapeutic targets for advanced HCC patients. Persistent injury to the liver as a result of insults such as hepatitis B or C viral (HBV or HCV) infections, alcohol abuse, and non-alcoholic fatty liver disease (NAFLD), results in chronic inflammation, which progresses to hepatic fibrosis and later, cirrhosis, provides the conditions for initiation of HCC. One of the key pathways studied for its role in inflammation and carcinogenesis is the eicosanoid pathway. In this review, we briefly outline the eicosanoid pathway, describe the mechanisms by which some pathway members either facilitate or counter the development of liver diseases, with the focus on NAFLD/hepatic fibrosis/cirrhosis, and HCC. We describe the link between the eicosanoid pathway, inflammation and these liver diseases, and identify components of the eicosanoid pathway that may be used as potential therapeutic targets in HCC.
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Affiliation(s)
- Anshuli Razdan
- School of Medicine, Western Sydney UniversitySydney, NSW, Australia
- Department of Medical Oncology, Ingham Institute for Applied Medical ResearchSydney, NSW, Australia
| | - Nathan M Main
- Gastroenterology and Liver Laboratory, Ingham Institute for Applied Medical ResearchSydney, NSW, Australia
| | - Vincent Chiu
- Gastroenterology and Liver Laboratory, Ingham Institute for Applied Medical ResearchSydney, NSW, Australia
| | - Nicholas A Shackel
- Gastroenterology and Liver Laboratory, Ingham Institute for Applied Medical ResearchSydney, NSW, Australia
| | - Paul de Souza
- School of Medicine, Western Sydney UniversitySydney, NSW, Australia
- Department of Medical Oncology, Ingham Institute for Applied Medical ResearchSydney, NSW, Australia
- School of Medicine, University of WollongongWollongong, NSW, Australia
| | - Katherine Bryant
- Gastroenterology and Liver Laboratory, Ingham Institute for Applied Medical ResearchSydney, NSW, Australia
| | - Kieran F Scott
- School of Medicine, Western Sydney UniversitySydney, NSW, Australia
- Department of Medical Oncology, Ingham Institute for Applied Medical ResearchSydney, NSW, Australia
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Flores E, Muñoz-Osses M, Torrent C, Vásquez-Martínez Y, Gómez A, Cortez-San Martin M, Vega A, Martí AA, Godoy F, Mascayano C. Design, Synthesis and Biological Evaluation of Ferrocenyl Thiazole and Thiazolo[5,4-d]thiazole Catechols as Inhibitors of 5-hLOX and as Antibacterials against Staphylococcus aureus. Structural Relationship and Computational Studies. Organometallics 2020. [DOI: 10.1021/acs.organomet.0c00284] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Affiliation(s)
| | | | | | - Yesseny Vásquez-Martínez
- Programa-Centro de Investigaciones Biomédicas y Aplicadas (CIBAP), Escuela de Medicina, Facultad de Ciencias Médicas, Universidad de Santiago de Chile, Santiago, Chile
| | | | | | - Andrés Vega
- Departamento de Ciencias Químicas, Facultad de Ecología y Recursos Naturales, Universidad Nacional Andrés Bello, República 275, Santiago Chile
| | - Angel A. Martí
- Department of Chemistry, Bioengineering and Materials Science & Nanoengineering, Rice University, Houston, Texas 77005, United States
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Finotello R, Schiavo L, Ressel L, Frohmader A, Silvestrini P, Verin R. Lipoxygenase-5 Expression in Canine Urinary Bladder: Normal Urothelium, Cystitis and Transitional Cell Carcinoma. J Comp Pathol 2019; 170:1-9. [PMID: 31375151 DOI: 10.1016/j.jcpa.2019.05.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 04/15/2019] [Accepted: 05/06/2019] [Indexed: 02/07/2023]
Abstract
Transitional cell carcinoma (TCC) is the most common canine urinary tract tumour and mimics human invasive TCC. Human TCCs overexpress lipoxygenase (LOX)-5 and the use of target inhibitors has proven effective in inhibiting neoplastic growth. In this study, we investigated the immunohistochemical expression of LOX-5 in normal canine urinary bladder, cystitis and TCC. The comparative expression of LOX-5, cyclo-oxygenase (COX)-1 and COX-2 among the three tissue groups was also examined. Biopsy samples from cases of cystitis and TCC were reviewed from 2012 to 2016; samples of histologically normal bladder were used as controls. Dogs were excluded if they had received glucocorticoids, non-steroidal anti-inflammatory drugs (NSAIDs) and/or chemotherapy prior to tissue collection. LOX-5 was expressed in 95% of TCCs, 23% of cases of cystitis and 10% of controls. LOX-5 and COX-2 immunohistochemistry scores were significantly (P <0.01) higher in TCCs versus cystitis and normal bladders. Results of this study support the rationale for further investigation of the use of NSAIDs with dual anti COX-2 and LOX-5 effect for the treatment of canine TCC.
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Affiliation(s)
- Riccardo Finotello
- Department of Small Animal Clinical Science, Institute of Veterinary Science, University of Liverpool, Leahurst Campus, Neston, UK.
| | - Luca Schiavo
- Department of Small Animal Clinical Science, Institute of Veterinary Science, University of Liverpool, Leahurst Campus, Neston, UK
| | - Lorenzo Ressel
- Department of Veterinary Pathology and Public Health, Institute of Veterinary Science, University of Liverpool, Leahurst Campus, Neston, UK
| | - Ava Frohmader
- Institute of Veterinary Science, University of Liverpool, Liverpool, UK
| | - Paolo Silvestrini
- Department of Small Animal Clinical Science, Institute of Veterinary Science, University of Liverpool, Leahurst Campus, Neston, UK
| | - Ranieri Verin
- Department of Veterinary Pathology and Public Health, Institute of Veterinary Science, University of Liverpool, Leahurst Campus, Neston, UK
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Choi S, Snider AJ. Diet, lipids and colon cancer. CELLULAR NUTRIENT UTILIZATION AND CANCER 2019; 347:105-144. [DOI: 10.1016/bs.ircmb.2019.07.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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Khophai S, Thanee M, Techasen A, Namwat N, Klanrit P, Titapun A, Jarearnrat A, Sa-Ngiamwibool P, Loilome W. Zileuton suppresses cholangiocarcinoma cell proliferation and migration through inhibition of the Akt signaling pathway. Onco Targets Ther 2018; 11:7019-7029. [PMID: 30410359 PMCID: PMC6198876 DOI: 10.2147/ott.s178942] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Background Inflammatory lipid mediators play an important role in several cancer types. Leukotrienes (LTs), pro-inflammatory lipid mediators, are involved in chronic inflammation and cancer progression. They are derived from arachidonic acid by 5-lipoxygenase (5-LOX) activity. On the other hand, 15-lipoxygenase (15-LOX-1) converts LTs into lipoxins (LXs), pro-resolving lipid mediators. LXs are involved in the attenuation of inflammation and cancer development. Purpose We aimed to investigate the lipid mediator pathways, especially the LTs and LXs pathways, by studying 5-LOX and 15-LOX-1 expression in human cholangiocarcinoma (CCA) tissue. We also investigated the efficiency of zileuton (5-LOX inhibitor) treatment and BML-111 (LXA4 analog) addition on CCA cell lines properties. Patients and methods The expression of 5-LOX and 15-LOX-1 in fifty human cholangiocarcinoma (CCA) tissue was analyzed using immunohistochemical staining. In addition, the effect of zileuton and BML-111 on CCA cell growth and migration was demonstrated using a cell viability assay and wound-healing assay, respectively. Furthermore, the molecular mechanism by which zileuton inhibits CCA cell migration was revealed using immunofluorescent staining and western blot analysis, respectively. Results We demonstrate that the upregulation of 5-LOX is significantly correlated with CCA recurrent status. A positive 15-LOX-1 signal was significantly associated with a longer survival time in CCA patients. We found that co-expression of 5-LOX and 15-LOX-1 resulted in a relatively good prognosis in CCA patients. In addition, zileuton could inhibit CCA cell migration as well as BML-111. Interestingly, zileuton treatment not only downregulated 5-LOX, but also upregulated 15-LOX-1, together with reversing the epithelial-mesenchymal transition to mesenchymal-epithelial transition phenotype as observed in EMT marker western blot. Conclusion These findings suggest that 5-LOX and 15-LOX-1 play a key role in CCA and may serve as targets for CCA therapy.
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Affiliation(s)
- Sasikamon Khophai
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand, .,Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand,
| | - Malinee Thanee
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand, .,Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand,
| | - Anchalee Techasen
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand, .,Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand
| | - Nisana Namwat
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand, .,Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand,
| | - Poramate Klanrit
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand, .,Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand,
| | - Attapol Titapun
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand, .,Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Apiwat Jarearnrat
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand, .,Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Prakasit Sa-Ngiamwibool
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand, .,Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Watcharin Loilome
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand, .,Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand,
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Abstract
Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death in the USA. It is of practical importance to identify novel therapeutic targets of CRC to develop new anti-cancer drugs and to discover novel biomarkers of CRC to develop new detection methods. Eicosanoids, which are metabolites of polyunsaturated fatty acids produced by cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) enzymes, are important lipid-signaling molecules involved in the regulation of inflammation and tumorigenesis. Substantial studies have shown that the profiles of eicosanoids are deregulated in CRC, and the enzymes, metabolites, and receptors in the eicosanoid signaling cascade play critical roles in regulating colonic inflammation and colon tumorigenesis. In this review, we discuss the roles of the COX, LOX, and CYP pathways in the carcinogenesis of CRC.
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Affiliation(s)
- Yuxin Wang
- College of Life Science, Northwest University, Xi'an, Shaanxi, China
- Department of Food Science, University of Massachusetts, Amherst, MA, USA
| | - Weicang Wang
- Department of Food Science, University of Massachusetts, Amherst, MA, USA
| | - Katherine Z Sanidad
- Department of Food Science, University of Massachusetts, Amherst, MA, USA
- Molecular and Cellular Biology Graduate Program, University of Massachusetts, Amherst, MA, USA
| | - Pei-An Shih
- Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA
| | - Xinfeng Zhao
- College of Life Science, Northwest University, Xi'an, Shaanxi, China
| | - Guodong Zhang
- Department of Food Science, University of Massachusetts, Amherst, MA, USA.
- Molecular and Cellular Biology Graduate Program, University of Massachusetts, Amherst, MA, USA.
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11
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González-Quezada BA, Santana-Bejarano UF, Corona-Rivera A, Pimentel-Gutiérrez HJ, Silva-Cruz R, Ortega-De-la-Torre C, Franco-Topete R, Franco-Topete K, Centeno-Flores MW, Maciel-Gutiérrez VM, Corona-Rivera JR, Armendáriz-Borunda J, Bobadilla-Morales L. Expression profile of NF-κB regulated genes in sporadic colorectal cancer patients. Oncol Lett 2018; 15:7344-7354. [PMID: 29849793 DOI: 10.3892/ol.2018.8201] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Accepted: 01/24/2018] [Indexed: 01/15/2023] Open
Abstract
Colorectal cancer (CRC) is the fourth leading worldwide cause of cancer-associated mortalities. Nuclear factor-κB (NF-κB) is a transcriptional regulator of multiple genes associated with CRC. Tumor tissue were compared with normal adjacent mucosa from 30 sporadic patients with CRC were investigated. A total of 8 non-CRC patients were analyzed as a control group. In the present study, the protein expression of NF-κB/p65 was detected by immunohistochemistry, and the gene expression profiles of cyclin D1 (CCND1), prostaglandin-endoperoxide synthase 2, vascular endothelial growth factor A, matrix metallopeptidase 9, BCL2 apoptosis regulator (BCL2), BCL2 like 1, nitric oxide synthase 2, tumor necrosis factor and arachidonate lipoxygenase were detected by reverse transcription-quantitative polymerase chain reaction. NF-κB/p65 and genes expression profiles were classified according to tumor-node-metastasis (TNM) clinicopathological parameters, followed by statistical analysis. Higher protein expression of NF-κB/p65 in the cytoplasm of tumor tissues compared with adjacent normal mucosa was reported; this increment was positively associated with all clinicopathological parameters, except for tumor localization site. The selected genes demonstrated a diverse associative pattern when analyzed with clinicopathological parameters. CCND1 was positively associated with all TNM parameters and BCL2 was negatively associated with all TNM parameters, thus indicating their importance as strong molecular biomarkers for CRC. According to these results, not all selected genes regulated by NF-κB/p65 show increased expression during CRC development, whereas the transcription factor did. The present study suggests that NF-κB/p65 overexpression is necessary for CRC establishment and progression, but its transcriptional activity is not sufficient to regulate all target genes in CRC. NF-κB/p65 and the gene expression profiles reported in the present study may be therapeutically useful. Considering the heterogeneity of the disease, the particular evaluation of these molecules may allow for the selection of proper diagnosis, treatment and follow-up for patients with sporadic CRC.
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Affiliation(s)
- Betsy Annel González-Quezada
- Cytogenetics and Genomics Laboratory, Human Genetic Institute 'Dr. Enrique Corona Rivera', University of Guadalajara, Guadalajara, Jalisco 44340, México.,Cytogenetics Unit, Pediatric Hematology and Oncology Service, Hospital Civil of Guadalajara 'Dr. Juan I. Menchaca', Guadalajara, Jalisco 44340, México
| | - Uriel Francisco Santana-Bejarano
- Cytogenetics and Genomics Laboratory, Human Genetic Institute 'Dr. Enrique Corona Rivera', University of Guadalajara, Guadalajara, Jalisco 44340, México.,Cytogenetics Unit, Pediatric Hematology and Oncology Service, Hospital Civil of Guadalajara 'Dr. Juan I. Menchaca', Guadalajara, Jalisco 44340, México
| | - Alfredo Corona-Rivera
- Cytogenetics and Genomics Laboratory, Human Genetic Institute 'Dr. Enrique Corona Rivera', University of Guadalajara, Guadalajara, Jalisco 44340, México.,Cytogenetics Unit, Pediatric Hematology and Oncology Service, Hospital Civil of Guadalajara 'Dr. Juan I. Menchaca', Guadalajara, Jalisco 44340, México
| | - Helia Judith Pimentel-Gutiérrez
- Cytogenetics and Genomics Laboratory, Human Genetic Institute 'Dr. Enrique Corona Rivera', University of Guadalajara, Guadalajara, Jalisco 44340, México.,Cytogenetics Unit, Pediatric Hematology and Oncology Service, Hospital Civil of Guadalajara 'Dr. Juan I. Menchaca', Guadalajara, Jalisco 44340, México
| | - Rocío Silva-Cruz
- Cytogenetics and Genomics Laboratory, Human Genetic Institute 'Dr. Enrique Corona Rivera', University of Guadalajara, Guadalajara, Jalisco 44340, México
| | - Citlalli Ortega-De-la-Torre
- Cytogenetics Unit, Pediatric Hematology and Oncology Service, Hospital Civil of Guadalajara 'Dr. Juan I. Menchaca', Guadalajara, Jalisco 44340, México
| | - Ramón Franco-Topete
- Pathological Anatomy Service, Hospital Civil of Guadalajara 'Dr. Juan I. Menchaca', Guadalajara, Jalisco 44340, México
| | - Karina Franco-Topete
- Pathological Anatomy Service, Hospital Civil of Guadalajara 'Dr. Juan I. Menchaca', Guadalajara, Jalisco 44340, México
| | | | - Víctor Manuel Maciel-Gutiérrez
- Colon and Rectum Service, Health Sciences University Center, University of Guadalajara, Guadalajara, Jalisco 44340, México
| | - Jorge Román Corona-Rivera
- Cytogenetics and Genomics Laboratory, Human Genetic Institute 'Dr. Enrique Corona Rivera', University of Guadalajara, Guadalajara, Jalisco 44340, México
| | - Juan Armendáriz-Borunda
- Molecular Biology and Gene Therapy Institute, Health Sciences University Center, University of Guadalajara, Guadalajara, Jalisco 44340, México
| | - Lucina Bobadilla-Morales
- Cytogenetics and Genomics Laboratory, Human Genetic Institute 'Dr. Enrique Corona Rivera', University of Guadalajara, Guadalajara, Jalisco 44340, México.,Cytogenetics Unit, Pediatric Hematology and Oncology Service, Hospital Civil of Guadalajara 'Dr. Juan I. Menchaca', Guadalajara, Jalisco 44340, México
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12
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Mandal P. Molecular signature of nitric oxide on major cancer hallmarks of colorectal carcinoma. Inflammopharmacology 2017; 26:331-336. [PMID: 29289998 DOI: 10.1007/s10787-017-0435-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Accepted: 12/11/2017] [Indexed: 11/28/2022]
Abstract
Colorectal cancer (CRC) is the one of the most important diseases throughout the world. Several aetiological risk factors, viz. sedentary life style, smoking, alcohol intake, less physical activity, red meat, and microbiota, are associated with the development of CRC. Molecular pathophysiology of CRC implies inflammation, metastasis, apotosis and angiogenesis. Inflammation involves interaction between various immune cells, inflammatory cells, chemokines, cytokines, and pro-inflammatory mediators, such as cyclooxygenase (COX) and lipoxygenase (LOX) pathways, which may lead to signalling towards, tumour cell proliferation, growth, and invasion whereas nitric oxide (NO) has been associated with metastasis, apoptosis, and angiogenesis. Therefore, this review emphasises on the potential molecular mechanisms associated with NO with alteration of cancer biomarkers during development of colorectal carcinogenesis.
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Affiliation(s)
- Paramita Mandal
- Department of Zoology, The University of Burdwan, Burdwan, India.
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13
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Sugai T, Takahashi Y, Eizuka M, Sugimoto R, Fujita Y, Habano W, Otsuka K, Sasaki A, Yamamoto E, Matsumoto T, Suzuki H. Molecular profiling and genome-wide analysis based on somatic copy number alterations in advanced colorectal cancers. Mol Carcinog 2017; 57:451-461. [PMID: 29230882 PMCID: PMC5814737 DOI: 10.1002/mc.22769] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Revised: 11/18/2017] [Accepted: 11/20/2017] [Indexed: 12/13/2022]
Abstract
To characterize somatic alterations in colorectal cancer (CRC), we conducted a genome-scale analysis of 106 CRC specimens. We assessed comprehensive somatic copy number alterations (SCNAs) in these CRC specimens. In addition, we examined microsatellite instability (MSI; low and high), genetic mutations (KRAS, BRAF, TP53, and PIK3CA), and DNA methylation status (classified into low, intermediate, and high type). We stratified molecular alterations in the CRCs using a hierarchical cluster analysis. The examined CRCs could be categorized into three subgroups using hierarchical cluster analysis. Tumors in subgroup 1 were characterized by a low frequency of SCNAs and a high frequency of MSI-high status, whereas tumors in subgroups 2 and 3 were closely associated with a high frequency of SCNAs. Tumors in subgroup 1 were preferentially present in the right-sided colon and showed frequent MSI-high status. Subgroup 3 was distinguished by specific alterations, including gains at 1q23-44, 1p11-36, 10q11-26, 10p11-13, 12q24-24, and 13q33-33. In contrast, tumors in subgroup 2 were characterized by copy-neutral LOH at 12p12-13, 1q24-25, and 10q22. In addition, KRAS mutations were more frequently found in subgroup 3 than in subgroup 1. TP53 mutations and intermediate levels of DNA methylation were common alterations in the three subgroups. SCNAs contributed to sporadic CRC, and there were three subgroups based on SCNAs that played a different role in driving the development of this disease.
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Affiliation(s)
- Tamotsu Sugai
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Yayoi Takahashi
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Makoto Eizuka
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Ryo Sugimoto
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Yasuko Fujita
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Wataru Habano
- Department of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, Morioka, Japan
| | - Kouki Otsuka
- Department of Surgery, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Akira Sasaki
- Department of Surgery, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Eiichiro Yamamoto
- Department of Molecular Biology, School of Medicine, Sapporo Medical University, Sapporo, Japan
| | - Takayuki Matsumoto
- Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Hiromu Suzuki
- Department of Molecular Biology, School of Medicine, Sapporo Medical University, Sapporo, Japan
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14
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Wang D, Li Y, Zhang C, Li X, Yu J. MiR‐216a‐3p inhibits colorectal cancer cell proliferation through direct targeting COX‐2 and ALOX5. J Cell Biochem 2017; 119:1755-1766. [DOI: 10.1002/jcb.26336] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Accepted: 08/07/2017] [Indexed: 12/19/2022]
Affiliation(s)
- Dongxia Wang
- Department of Radiation OncologyShandong Cancer Hospital Affiliated to Shandong UniversityJinanChina
- Department of Radiation OncologyDongguan People's HospitalDongguanChina
| | - Yuechun Li
- Department of Gastrointestinal SurgeryDongguan People's HospitalDongguanChina
| | - Chun Zhang
- Department of Radiation OncologyDongguan People's HospitalDongguanChina
| | - Xianming Li
- Department of Radiation OncologyShenzhen People's HospitalShenzhenChina
| | - Jinming Yu
- Department of Radiation OncologyShandong Cancer Hospital Affiliated to Shandong UniversityJinanChina
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15
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Shen FQ, Wang ZC, Wu SY, Ren SZ, Man RJ, Wang BZ, Zhu HL. Synthesis of novel hybrids of pyrazole and coumarin as dual inhibitors of COX-2 and 5-LOX. Bioorg Med Chem Lett 2017; 27:3653-3660. [PMID: 28720504 DOI: 10.1016/j.bmcl.2017.07.020] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2017] [Revised: 07/05/2017] [Accepted: 07/06/2017] [Indexed: 12/27/2022]
Abstract
In our previous study, we designed a series of pyrazole derivatives as novel COX-2 inhibitors. In order to obtain novel dual inhibitors of COX-2 and 5-LOX, herein we designed and synthesized 20 compounds by hybridizing pyrazole with substituted coumarin who was reported to exhibit 5-LOX inhibition to select potent compounds using adequate biological trials sequentially including selective inhibition of COX-2 and 5-LOX, anti-proliferation in vitro, cells apoptosis and cell cycle. Among them, the most potent compound 11g (IC50=0.23±0.16μM for COX-2, IC50=0.87±0.07μM for 5-LOX, IC50=4.48±0.57μM against A549) showed preliminary superiority compared with the positive controls Celecoxib (IC50=0.41±0.28μM for COX-2, IC50=7.68±0.55μM against A549) and Zileuton (IC50=1.35±0.24μM for 5-LOX). Further investigation confirmed that 11g could induce human non-small cell lung cancer A549 cells apoptosis and arrest the cell cycle at G2 phase in a dose-dependent manner. Our study might contribute to COX-2, 5-LOX dual inhibitors thus exploit promising novel cancer prevention agents.
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Affiliation(s)
- Fa-Qian Shen
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210046, People's Republic of China; Elion Nature Biological Technology Co., Ltd, 16 Hengtong Road, Nanjing 210038, People's Republic of China
| | - Zhong-Chang Wang
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210046, People's Republic of China; Elion Nature Biological Technology Co., Ltd, 16 Hengtong Road, Nanjing 210038, People's Republic of China
| | - Song-Yu Wu
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210046, People's Republic of China; Elion Nature Biological Technology Co., Ltd, 16 Hengtong Road, Nanjing 210038, People's Republic of China
| | - Shen-Zhen Ren
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210046, People's Republic of China; Elion Nature Biological Technology Co., Ltd, 16 Hengtong Road, Nanjing 210038, People's Republic of China
| | - Ruo-Jun Man
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210046, People's Republic of China; Elion Nature Biological Technology Co., Ltd, 16 Hengtong Road, Nanjing 210038, People's Republic of China
| | - Bao-Zhong Wang
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210046, People's Republic of China; Elion Nature Biological Technology Co., Ltd, 16 Hengtong Road, Nanjing 210038, People's Republic of China
| | - Hai-Liang Zhu
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210046, People's Republic of China; Elion Nature Biological Technology Co., Ltd, 16 Hengtong Road, Nanjing 210038, People's Republic of China.
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Bisindolylmaleimide alkaloid BMA-155Cl induces autophagy and apoptosis in human hepatocarcinoma HepG-2 cells through the NF-κB p65 pathway. Acta Pharmacol Sin 2017; 38:524-538. [PMID: 28260799 DOI: 10.1038/aps.2016.171] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Accepted: 12/28/2016] [Indexed: 12/23/2022]
Abstract
Bisindolylmaleimides, a series of derivatives of a PKC inhibitor staurosporine, exhibit potential as anti-cancer drugs and have received considerable attention in clinical trials. This study aims to investigate the effects of a bisindolylmaleimide alkaloid 155Cl (BMA-155Cl) with a novel structure on autophagy and apoptosis in human hepatocarcinoma HepG-2 cells in vitro and in vivo. The cell poliferation was assessed with a MTT assay. Autophagy was evaluated by MDC staining and TEM analysis. Apoptosis was investigated using Annexin V-FITC/PI and DAPI staining. The antitumor effects were further evaluated in nude mice bearing HepG-2 xenografts, which received BMA-155Cl (10, 20 mg/kg, ip) for 18 days. Autophagy- and apoptosis-associated proteins and their mRNA levels were examined with Western blotting, immunohistochemistry, and RT-PCR. BMA-155Cl (2.5-20 μmol/L) inhibited the growth of HepG-2 cells with IC50 values of 16.62±1.34, 12.21±0.83, and 8.44±1.82 μmol/L at 24, 48, and 72 h, respectively. Furthermore, BMA-155Cl (5-20 μmol/L) dose-dependently induced autophagy and apoptosis in HepG-2 cells. The formation of autophagic vacuoles was induced by BMA-155Cl (10 μmol/L) at approximately 6 h and peaked at approximately 15 h. Pretreatment with 3-MA potentiated BMA-155Cl-mediated apoptotic cell death. This compound dose-dependently increased the mRNA and protein levels of Beclin-1, NF-κB p65, p53, and Bax, but decreased the expression of IκB and Bcl-2. Pretreatment with BAY 11-7082, a specific inhibitor of NF-κB p65, blocked BMA-155Cl-induced expression of autophagy- and apoptosis-associated proteins. BMA-155Cl administration effectively suppressed the growth of HepG-2 xenografts in vivo, and increased the protein expression levels of LC3B, Beclin-1, NF-κB p65, and Bax in vivo. We conclude that the NF-κB p65 pathway is involved in BMA-155Cl-triggered autophagy, followed by apoptosis in HepG-2 cells in vitro and in vivo. Hence, BMA-155Cl could be a promising pro-apoptotic candidate for developing as a novel anti-cancer drug.
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17
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Moreno JJ. Eicosanoid receptors: Targets for the treatment of disrupted intestinal epithelial homeostasis. Eur J Pharmacol 2016; 796:7-19. [PMID: 27940058 DOI: 10.1016/j.ejphar.2016.12.004] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Revised: 11/30/2016] [Accepted: 12/05/2016] [Indexed: 12/25/2022]
Abstract
The importance of cyclooxygenase and lipoxygenase pathways and the consequent eicosanoid synthesis in the physiology and pathophysiology of the intestinal epithelium is currently being established. Each eicosanoid (prostanoid, leukotriene, hydroxyeicosatetraenoic acid) preferentially recognizes one or more receptors coupled to one or more signal-transduction processes. This overview focuses on the role of eicosanoid receptors in the maintenance of intestinal epithelium physiology through the control of proliferation/differentiation/apoptosis processes. Furthermore, it is reported that the role of these receptors on the regulation of the barrier function of the intestinal epithelium have arisen through the regulation of absorption/secretion processes, tight-junction state and the control of the intestinal immune response. Also, this review considers the implication of AA cascade in the disruption of epithelial homeostasis during inflammatory bowel diseases and colorectal cancer as well as the therapeutic values and potential of the eicosanoid receptors as novel targets for the treatments of the pathologies above mentioned.
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Affiliation(s)
- Juan J Moreno
- Department of Nutrition, Food Sciences and Gastronomy, Faculty of Pharmacy and Food Sciences, Institute of Nutrition and Food Safety (INSA-UB), University of Barcelona, Avda. Prat de la Riba 171, E-08921 Santa Coloma de Gramenet, Spain.
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18
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Synthesis and evaluation of chromone-2-carboxamide derivatives as cytotoxic agents and 5-lipoxygenase inhibitors. Med Chem Res 2016. [DOI: 10.1007/s00044-016-1691-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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Rajabian A, Boroushaki MT, Hayatdavoudi P, Sadeghnia HR. Boswellia serrata Protects Against Glutamate-Induced Oxidative Stress and Apoptosis in PC12 and N2a Cells. DNA Cell Biol 2016; 35:666-679. [PMID: 27494534 DOI: 10.1089/dna.2016.3332] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
This study was designed to investigate whether the extract from Boswellia serrata oleo-gum resin (BSE) can protect against glutamate-induced oxidative damage and cytotoxicity in PC12 and N2a cell lines. Using a simple and reliable reverse-phase high-performance liquid chromatography (HPLC), the amount of 3-acetyl-11-keto-β-boswellic acid (AKBA) in the BSE was found to be 18.5% w/w. The results confirmed that BSE and AKBA, at concentrations as high as 100 μg/mL or 10 μM, respectively, caused no significant cytotoxicity or apoptotic cell death. Co- and pretreatment with BSE (25-100 μg/mL) or AKBA (5 μM) restored the viability of PC12 and N2a cells under glutamate toxicity (8 mM). Treatment with BSE and AKBA also attenuated the toxic effects of glutamate on intracellular reactive oxygen species, lipid peroxidation, superoxide dismutase activity, and oxidative DNA damage compared with the untreated glutamate-injured cells. Furthermore, BSE and AKBA decreased the apoptotic cell population in the sub-G1 region and the rate of both early and late-stage apoptosis induced by glutamate in the cells. Our data suggest that the protective effects of Boswellia extract and AKBA against glutamate toxicity in PC12 and N2a cells may be mediated through the amelioration of the oxidative stress and the resultant apoptosis.
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Affiliation(s)
- Arezoo Rajabian
- 1 Department of Pharmacology, Faculty of Medicine, Mashhad University of Medical Sciences , Mashhad, Iran
| | - Mohammad Taher Boroushaki
- 1 Department of Pharmacology, Faculty of Medicine, Mashhad University of Medical Sciences , Mashhad, Iran .,2 Pharmacological Research Center of Medicinal Plants, Faculty of Medicine, Mashhad University of Medical Sciences , Mashhad, Iran
| | - Parichehr Hayatdavoudi
- 3 Neurogenic Inflammation Research Center, Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences , Mashhad, Iran
| | - Hamid Reza Sadeghnia
- 1 Department of Pharmacology, Faculty of Medicine, Mashhad University of Medical Sciences , Mashhad, Iran .,2 Pharmacological Research Center of Medicinal Plants, Faculty of Medicine, Mashhad University of Medical Sciences , Mashhad, Iran .,4 Neurocognitive Research Center, Faculty of Medicine, Mashhad University of Medical Sciences , Mashhad, Iran
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Chandrasekharan JA, Marginean A, Sharma-Walia N. An insight into the role of arachidonic acid derived lipid mediators in virus associated pathogenesis and malignancies. Prostaglandins Other Lipid Mediat 2016; 126:46-54. [PMID: 27450483 DOI: 10.1016/j.prostaglandins.2016.07.009] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2016] [Revised: 06/25/2016] [Accepted: 07/18/2016] [Indexed: 12/14/2022]
Abstract
Several studies shed light on the size and diversity of the lipidome, along with its role in physiological and pathological processes in human health. Besides that, lipids also function as important signaling mediators. This review focuses on discussing the role of arachidonic acid (AA) derived lipids as mediators in diseases with special emphasis on viral infections. Structurally, arachidonic acid derived lipids, also referred to as lipid mediators, can be classified into three specific classes: Class 1-eicosanoids derived from arachidonic acid metabolism; Class 2-lysophospholipids consisting of either a glycerol or a sphingosine backbone; Class 3-AA and ω-3 polyunsaturated fatty acid (PUFA) derivatives. Class 1 and 2 lipids are commonly referred to as pro-inflammatory molecules, which are found upregulated in diseases like cancer and viral infection. Class 3 lipids are anti-inflammatory molecules, which could be potentially used in treatment of diseases associated with inflammation. The function of each class has been elucidated as unique and contributory to an overall cellular homeostasis. Current work in this field is promising and will surely usher in a new era of lipid understanding and control not only at the molecular level, but also in terms of holistic patient care.
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Affiliation(s)
- Jayashree A Chandrasekharan
- Department of Microbiology and Immunology, H.M. Bligh Cancer Research Laboratories, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA
| | - Alexandru Marginean
- Department of Microbiology and Immunology, H.M. Bligh Cancer Research Laboratories, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA
| | - Neelam Sharma-Walia
- Department of Microbiology and Immunology, H.M. Bligh Cancer Research Laboratories, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA.
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Cai H, Huang X, Xu S, Shen H, Zhang P, Huang Y, Jiang J, Sun Y, Jiang B, Wu X, Yao H, Xu J. Discovery of novel hybrids of diaryl-1,2,4-triazoles and caffeic acid as dual inhibitors of cyclooxygenase-2 and 5-lipoxygenase for cancer therapy. Eur J Med Chem 2016; 108:89-103. [DOI: 10.1016/j.ejmech.2015.11.013] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Revised: 10/16/2015] [Accepted: 11/06/2015] [Indexed: 12/13/2022]
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Roos J, Grösch S, Werz O, Schröder P, Ziegler S, Fulda S, Paulus P, Urbschat A, Kühn B, Maucher I, Fettel J, Vorup-Jensen T, Piesche M, Matrone C, Steinhilber D, Parnham MJ, Maier TJ. Regulation of tumorigenic Wnt signaling by cyclooxygenase-2, 5-lipoxygenase and their pharmacological inhibitors: A basis for novel drugs targeting cancer cells? Pharmacol Ther 2016; 157:43-64. [PMID: 26549540 DOI: 10.1016/j.pharmthera.2015.11.001] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Tuncer S, Banerjee S. Eicosanoid pathway in colorectal cancer: Recent updates. World J Gastroenterol 2015; 21:11748-11766. [PMID: 26557000 PMCID: PMC4631974 DOI: 10.3748/wjg.v21.i41.11748] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 06/25/2015] [Accepted: 08/31/2015] [Indexed: 02/06/2023] Open
Abstract
Enzymatic metabolism of the 20C polyunsaturated fatty acid (PUFA) arachidonic acid (AA) occurs via the cyclooxygenase (COX) and lipoxygenase (LOX) pathways, and leads to the production of various bioactive lipids termed eicosanoids. These eicosanoids have a variety of functions, including stimulation of homeostatic responses in the cardiovascular system, induction and resolution of inflammation, and modulation of immune responses against diseases associated with chronic inflammation, such as cancer. Because chronic inflammation is essential for the development of colorectal cancer (CRC), it is not surprising that many eicosanoids are implicated in CRC. Oftentimes, these autacoids work in an antagonistic and highly temporal manner in inflammation; therefore, inhibition of the pro-inflammatory COX-2 or 5-LOX enzymes may subsequently inhibit the formation of their essential products, or shunt substrates from one pathway to another, leading to undesirable side-effects. A better understanding of these different enzymes and their products is essential not only for understanding the importance of eicosanoids, but also for designing more effective drugs that solely target the inflammatory molecules found in both chronic inflammation and cancer. In this review, we have evaluated the cancer promoting and anti-cancer roles of different eicosanoids in CRC, and highlighted the most recent literature which describes how those molecules affect not only tumor tissue, but also the tumor microenvironment. Additionally, we have attempted to delineate the roles that eicosanoids with opposing functions play in neoplastic transformation in CRC through their effects on proliferation, apoptosis, motility, metastasis, and angiogenesis.
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Zick SM, Turgeon DK, Ren J, Ruffin MT, Wright BD, Sen A, Djuric Z, Brenner DE. Pilot clinical study of the effects of ginger root extract on eicosanoids in colonic mucosa of subjects at increased risk for colorectal cancer. Mol Carcinog 2015; 54:908-15. [PMID: 24760534 PMCID: PMC4208969 DOI: 10.1002/mc.22163] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2013] [Revised: 03/21/2014] [Accepted: 03/27/2014] [Indexed: 12/24/2022]
Abstract
Colorectal cancer (CRC) remains a significant cause of mortality. Inhibitors of cyclooxygenase (COX) and thus prostaglandin E2, are promising CRC preventives, but have significant toxicities. Ginger has been shown to inhibit COX, to decrease the incidence and multiplicity of adenomas, and decrease PGE2 concentrations in subjects at normal risk for CRC. This study was conducted to determine the effects of 2.0 g/d of ginger given orally on the levels of PGE2, leukotriene B4 (LTB4), 13-hydroxy-octadecadienoic acids, and 5-, 12-, & 15-hydroxyeicosatetraenoic acid, in the colonic mucosa of subjects at increased risk for CRC. We randomized 20 subjects to 2.0 g/d ginger or placebo for 28 d. At baseline and Day 28, a flexible sigmoidoscopy was used to obtain colon biopsies. A liquid chromatography mass spectrometry method was used to determine eicosanoid levels in the biopsies, and levels were expressed per amount of protein or free arachidonic acid (AA). There was a significant decrease in AA between baseline and Day 28 (P = 0.05) and significant increase in LTB4 (P = 0.04) when normalized to protein, in subjects treated with ginger versus placebo. No other changes in eicosanoids were observed. There was no difference between the groups in total adverse events (AE; P = 0.06). Ginger lacks the ability to decrease eicosanoid levels in people at increased risk for CRC. Ginger did appear to be both tolerable and safe; and could have chemopreventive effects through other mechanisms. Further investigation should focus on other markers of CRC risk in those at increased CRC risk.
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Affiliation(s)
- Suzanna M Zick
- Department of Family Medicine, University of Michigan Medical School, Ann Arbor, Michigan
- University of Micihgan School of Public Health Department of Enviromental Health Sciences, Ann Arbor, Michigan
| | - D Kim Turgeon
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan
| | - Jianwei Ren
- Department of Family Medicine, University of Michigan Medical School, Ann Arbor, Michigan
| | - Mack T Ruffin
- Department of Family Medicine, University of Michigan Medical School, Ann Arbor, Michigan
| | - Benjamin D Wright
- Department of Family Medicine, University of Michigan Medical School, Ann Arbor, Michigan
| | - Ananda Sen
- Department of Family Medicine, University of Michigan Medical School, Ann Arbor, Michigan
| | - Zora Djuric
- Department of Family Medicine, University of Michigan Medical School, Ann Arbor, Michigan
- University of Micihgan School of Public Health Department of Enviromental Health Sciences, Ann Arbor, Michigan
| | - Dean E Brenner
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan
- Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan
- VA Medical Center, Ann Arbor, Michigan
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25
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Mocellin MC, Camargo CQ, Nunes EA, Fiates GMR, Trindade EBSM. A systematic review and meta-analysis of the n-3 polyunsaturated fatty acids effects on inflammatory markers in colorectal cancer. Clin Nutr 2015; 35:359-369. [PMID: 25982417 DOI: 10.1016/j.clnu.2015.04.013] [Citation(s) in RCA: 86] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2014] [Revised: 01/21/2015] [Accepted: 04/23/2015] [Indexed: 12/14/2022]
Abstract
BACKGROUND Cancer and inflammation are closely related and an exacerbated inflammatory process can lead to tumor progression and a worse prognosis for the patient with cancer. Scientific literature has shown evidence that n-3 polyunsaturated fatty acids (PUFA) have anti-inflammatory action, and for this reason could be useful as an adjuvant in the treatment of some cancers. OBJECTIVE A systematic review and meta-analysis of the literature was conducted until September, 2014, to evaluate the effects of n-3 PUFA on inflammatory mediators in colorectal cancer (CRC) patients. PATIENTS AND METHODS Clinical trials were systematically searched in three electronic databases and screening reference lists. Random meta-analysis model was used to calculate the overall and stratified effect sizes. RESULTS Nine trials, representing 475 patients with CRC, evaluated effects of n-3 PUFA on cytokines (n = 6) and/or acute phase proteins (n = 5) levels. n-3 PUFA reduce the levels of IL-6 (SMD -2.34; 95% CI -4.37, -0.31; p = 0.024) and increase albumin (SMD 0.31; 95% CI 0.06, 0.56; p = 0.014) in overall analyses. In stratified analyses, reduction in IL-6 levels occurs in surgical patients that received 0.2 g/kg of fish oil parenterally at postoperative period (SMD -0.65; 95% CI -1.06, -0.24; p = 0.002), while, increase in albumin concentration occurs in surgical patients that received ≥ 2.5 g/d of EPA + DHA orally at preoperative period (SMD 0.34; 95% CI 0.02, 0.66; p = 0.038). In patients undergoing chemotherapy, the supplementation of 0.6 g/d of EPA + DHA during 9 week reduces CRP levels (SMD -0.95; 95% CI -1.73, -0.17; p = 0.017), and CRP/albumin ratio (SMD -0.95; 95% CI -1.73, -0.18; p = 0.016). CONCLUSIONS The results suggest benefits on some inflammatory mediators with the use of n-3 PUFA on CRC patients, but these benefits are specific to certain supplementation protocols involving duration, dose and route of administration, and also, the concomitant anti-cancer treatment adopted.
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Affiliation(s)
- Michel C Mocellin
- Department of Nutrition, Graduate Program in Nutrition, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil
| | - Carolina Q Camargo
- Department of Nutrition, Graduate Program in Nutrition, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil
| | - Everson Araujo Nunes
- Departament of Physiology, Laboratory of Investigation in Chronic Diseases, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil
| | - Giovanna M R Fiates
- Department of Nutrition, Graduate Program in Nutrition, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil
| | - Erasmo B S M Trindade
- Department of Nutrition, Graduate Program in Nutrition, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil.
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Misra S, Ghatak S, Vyas A, O’Brien P, Markwald RR, Khetmalas M, Hascall VC, McCarthy JB, Karamanos NK, Tammi MI, Tammi RH, Prestwitch GD, Padhye S. Isothiocyanate analogs targeting CD44 receptor as an effective strategy against colon cancer. Med Chem Res 2014; 23:3836-3851. [PMID: 25013352 PMCID: PMC4084864 DOI: 10.1007/s00044-014-0958-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Inflammatory pathway plays an important role in tumor cell progression of colorectal cancers. Although colon cancer is considered as one of the leading causes of death worldwide, very few drugs are available for its effective treatment. Many studies have examined the effects of specific COX-2 and 5-LOX inhibitors on human colorectal cancer, but the role of isothiocyanates (ITSCs) as COX-LOX dual inhibitors engaged in hyaluronan-CD44 interaction has not been studied. In the present work, we report series of ITSC analogs incorporating bioisosteric thiosemicarbazone moiety. These inhibitors are effective against panel of human colon cancer cell lines including COX-2 positive HCA-7, HT-29 cells lines, and hyaluronan synthase-2 (Has2) enzyme over-expressing transformed intestinal epithelial Apc10.1Has2 cells. Specifically, our findings indicate that HA-CD44v6-mediated COX-2/5-LOX signaling mediate survivin production, which in turn, supports anti-apoptosis and chemo-resistance leading to colon cancer cell survival. The over-expression of CD44v6shRNA as well as ITSC treatment significantly decreases the survival of colon cancer cells. The present results thus offer an opportunity to evolve potent inhibitors of HA synthesis and CD44v6 pathway and thus underscoring the importance of the ITSC analogs as chemopreventive agents for targeting HA/CD44v6 pathway.
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Affiliation(s)
- Suniti Misra
- Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Shibnath Ghatak
- Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Alok Vyas
- ISTRA, Department of Chemistry, Abeda Inamdar College, University of Pune, Pune 411001, India
- Department of Bioinformatics and Computer Science, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade, Pune 411033, India
| | - Paul O’Brien
- Hematology/Oncology Division, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Roger R. Markwald
- Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Madhukar Khetmalas
- Department of Bioinformatics and Computer Science, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade, Pune 411033, India
| | - Vincent C. Hascall
- Department of Biomedical Engineering/ND20, The Cleveland Clinic Foundation, Cleveland, OH, USA
| | - James B. McCarthy
- Department of Laboratory Medicine and Pathology, University of Minnesota Masonic Cancer Center, Minneapolis, MN, USA
| | - Nikos K. Karamanos
- Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece
| | - Markku I. Tammi
- University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland
| | - Raija H. Tammi
- University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland
| | - Glenn D. Prestwitch
- Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT, USA
| | - Subhash Padhye
- ISTRA, Department of Chemistry, Abeda Inamdar College, University of Pune, Pune 411001, India
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27
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Zhang H, Lei Y, Yuan P, Li L, Luo C, Gao R, Tian J, Feng Z, Nice EC, Sun J. ROS-mediated autophagy induced by dysregulation of lipid metabolism plays a protective role in colorectal cancer cells treated with gambogic acid. PLoS One 2014; 9:e96418. [PMID: 24810758 PMCID: PMC4014500 DOI: 10.1371/journal.pone.0096418] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2013] [Accepted: 04/07/2014] [Indexed: 12/26/2022] Open
Abstract
Gambogic acid (GA), the main active component of gamboge resin, has potent antitumor activity both in vivo and in vitro. However, the underlying molecular mechanisms remain unclear. In this study, we found that GA could initiate autophagy in colorectal cancer cells, and inhibition of the autophagy process accelerated the effect of proliferative inhibition and apoptotic cell death induced by GA, implying a protective role of autophagy. Two-dimensional electrophoresis-based proteomics showed that GA treatment altered the expression of multiple proteins involved in redox signaling and lipid metabolism. Functional studies revealed that GA-induced dysregulation of lipid metabolism could activate 5-lipoxygenase (5-LOX), resulting in intracellular ROS accumulation, followed by inhibition of Akt-mTOR signaling and autophagy initiation. Finally, results using a xenograft model suggested ROS-induced autophagy protect against the antitumor effect of GA. Taken together, these data showed new biological activities of GA against colorectal cancer underlying the protective role of ROS-induced autophagy. This study will provide valuable insights for future studies regarding the anticancer mechanisms of GA.
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Affiliation(s)
- Haiyuan Zhang
- Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of science and Technology, Wuhan, People's Republic of China
| | - Yunlong Lei
- Department of Biochemistry and Molecular Biology, and Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, China
| | - Ping Yuan
- Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of science and Technology, Wuhan, People's Republic of China
| | - Lingjun Li
- Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of science and Technology, Wuhan, People's Republic of China
| | - Chao Luo
- Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of science and Technology, Wuhan, People's Republic of China
| | - Rui Gao
- Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of science and Technology, Wuhan, People's Republic of China
| | - Jun Tian
- Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of science and Technology, Wuhan, People's Republic of China
| | - Zuohua Feng
- Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of science and Technology, Wuhan, People's Republic of China
| | - Edouard C Nice
- Monash University, Department of Biochemistry and Molecular Biology, Clayton, Victoria, Australia
| | - Jun Sun
- Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of science and Technology, Wuhan, People's Republic of China
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Cesari IM, Carvalho E, Figueiredo Rodrigues M, Mendonça BDS, Amôedo ND, Rumjanek FD. Methyl jasmonate: putative mechanisms of action on cancer cells cycle, metabolism, and apoptosis. Int J Cell Biol 2014; 2014:572097. [PMID: 24648844 PMCID: PMC3933403 DOI: 10.1155/2014/572097] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2013] [Revised: 11/06/2013] [Accepted: 11/07/2013] [Indexed: 12/29/2022] Open
Abstract
Methyl jasmonate (MJ), an oxylipid that induces defense-related mechanisms in plants, has been shown to be active against cancer cells both in vitro and in vivo, without affecting normal cells. Here we review most of the described MJ activities in an attempt to get an integrated view and better understanding of its multifaceted modes of action. MJ (1) arrests cell cycle, inhibiting cell growth and proliferation, (2) causes cell death through the intrinsic/extrinsic proapoptotic, p53-independent apoptotic, and nonapoptotic (necrosis) pathways, (3) detaches hexokinase from the voltage-dependent anion channel, dissociating glycolytic and mitochondrial functions, decreasing the mitochondrial membrane potential, favoring cytochrome c release and ATP depletion, activating pro-apoptotic, and inactivating antiapoptotic proteins, (4) induces reactive oxygen species mediated responses, (5) stimulates MAPK-stress signaling and redifferentiation in leukemia cells, (6) inhibits overexpressed proinflammatory enzymes in cancer cells such as aldo-keto reductase 1 and 5-lipoxygenase, and (7) inhibits cell migration and shows antiangiogenic and antimetastatic activities. Finally, MJ may act as a chemosensitizer to some chemotherapics helping to overcome drug resistant. The complete lack of toxicity to normal cells and the rapidity by which MJ causes damage to cancer cells turn MJ into a promising anticancer agent that can be used alone or in combination with other agents.
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Affiliation(s)
- Italo Mario Cesari
- Laboratório de Bioquímica e Biologia Molecular do Câncer, Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Avenida Carlos Chagas Filho 373, Prédio CCS, Bloco E, Sala 22, Ilha do Fundão, Cidade Universitária, 21941-902 Rio de Janeiro, RJ, Brazil
| | - Erika Carvalho
- Laboratório de Bioquímica e Biologia Molecular do Câncer, Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Avenida Carlos Chagas Filho 373, Prédio CCS, Bloco E, Sala 22, Ilha do Fundão, Cidade Universitária, 21941-902 Rio de Janeiro, RJ, Brazil
| | - Mariana Figueiredo Rodrigues
- Laboratório de Bioquímica e Biologia Molecular do Câncer, Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Avenida Carlos Chagas Filho 373, Prédio CCS, Bloco E, Sala 22, Ilha do Fundão, Cidade Universitária, 21941-902 Rio de Janeiro, RJ, Brazil
| | - Bruna dos Santos Mendonça
- Laboratório de Bioquímica e Biologia Molecular do Câncer, Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Avenida Carlos Chagas Filho 373, Prédio CCS, Bloco E, Sala 22, Ilha do Fundão, Cidade Universitária, 21941-902 Rio de Janeiro, RJ, Brazil
| | - Nivea Dias Amôedo
- Laboratório de Bioquímica e Biologia Molecular do Câncer, Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Avenida Carlos Chagas Filho 373, Prédio CCS, Bloco E, Sala 22, Ilha do Fundão, Cidade Universitária, 21941-902 Rio de Janeiro, RJ, Brazil
| | - Franklin David Rumjanek
- Laboratório de Bioquímica e Biologia Molecular do Câncer, Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Avenida Carlos Chagas Filho 373, Prédio CCS, Bloco E, Sala 22, Ilha do Fundão, Cidade Universitária, 21941-902 Rio de Janeiro, RJ, Brazil
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29
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Pimenta CAM, Latini FRM, DE Lima JM, DA Silva TD, Felipe AV, DE Lima Pazine VM, Forones NM. Study of the polymorphisms of cyclooxygenase-2 (-765G>C) and 5-lipoxygenase (1708G>A) in patients with colorectal cancer. Oncol Lett 2014; 7:513-518. [PMID: 24396479 PMCID: PMC3881951 DOI: 10.3892/ol.2013.1732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2013] [Accepted: 11/22/2013] [Indexed: 11/09/2022] Open
Abstract
Colorectal cancer (CRC) is the fourth most common cause of cancer-related mortality worldwide. Genetic alterations have been associated with an increased risk of cancer and greater tumor aggressiveness. Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) genes are important in cell cycle regulation, tumor growth and prostaglandin synthesis. The aim of the present study was to investigate the association between polymorphisms in the COX-2 and 5-LOX genes and the risk of CRC. A case-control study was conducted in patients with CRC matched for gender and age to a control group. DNA was extracted from peripheral leukocytes, and the polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism and gene sequencing. A specific questionnaire was applied to evaluate smoking, excessive alcohol consumption, physical activity, non-steroidal anti-inflammatory drug use and meat, fiber and fat intake. A total of 185 patients with CRC and 146 controls were studied. The heterozygous GC genotype of the COX-2 gene polymorphism was the most common in the two groups (60.0% in CRC patients and 52.7% in controls). The CC genotype was associated with an increased risk of CRC (odds ratio, 3.63; 95% confidence interval, 1.31–10.1; P=0.013). The homozygous wild-type genotype of the 5-LOX gene polymorphism was detected in 72.4% of the CRC patients and in 71.2% of the control subjects. The homozygous mutant genotype (CC) of the COX-2 gene is an independent risk factor for CRC. No association was found between 5-LOX genotypes and CRC.
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Affiliation(s)
| | | | | | | | - Aledson Vitor Felipe
- Gastroenterology Division, Federal University of São Paulo, São Paulo 04023900, Brazil
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30
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Ghatak S, Vyas A, Misra S, O'Brien P, Zambre A, Fresco VM, Markwald RR, Swamy KV, Afrasiabi Z, Choudhury A, Khetmalas M, Padhye S. Novel di-tertiary-butyl phenylhydrazones as dual cyclooxygenase-2/5-lipoxygenase inhibitors: synthesis, COX/LOX inhibition, molecular modeling, and insights into their cytotoxicities. Bioorg Med Chem Lett 2013; 24:317-24. [PMID: 24295787 DOI: 10.1016/j.bmcl.2013.11.015] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2013] [Revised: 10/24/2013] [Accepted: 11/08/2013] [Indexed: 11/17/2022]
Abstract
Although dual inhibition of Cyclooxygenase-2 (COX-2) and 5-Lipoxygenase (5-LOX) enzymes is highly effective than targeting COX or LOX alone, there are only a few reports of examining such compounds in case of colorectal cancers (CRC). In the present work we report that the novel di-tert-butyl phenol-based dual inhibitors DTPSAL, DTPBHZ, DTPINH, and DTPNHZ exhibit significant cytotoxicity against human CRC cell lines. Molecular docking studies revealed a good fit of these compounds in the COX-2 and 5-LOX protein cavities. The inhibitors show significant inhibition of COX-2 and 5-LOX activities and are effective against a panel of human colon cancer cell lines including HCA-7, HT-29, SW480 and intestinal Apc10.1 cells as well as the hyaluronan synthase-2 (Has2) enzyme over-expressing colon cancer cells, through inhibition of the Hyaluronan/CD44v6 cell survival pathway. Western blot analysis and qRT-PCR analyses indicated that the di-tert-butyl phenol-based dual inhibitors reduce the expression of COX-2, 5-LOX, and CD44v6 in human colon cancer HCA-7 cells, while the combination of CD44v6shRNA and DTPSAL has an additional inhibitory effect on CD44v6 mRNA expression. The synergistic inhibitory effect of Celecoxib and Licofelone on CD44v6 mRNA expression suggests that the present dual inhibitors down-regulate cyclooxygenase and lipoxygenase enzymes through CD44v6. The compounds also exhibited enhanced antiproliferative potency compared to standard dual COX/LOX inhibitor, viz. Licofelone. Importantly, the HA/CD44v6 antagonist CD44v6shRNA in combination with synthetic compounds had a sensitizing effect on the cancer cells which enhanced their antiproliferative potency, a finding which is crucial for the anti-proliferative potency of the novel synthetic di-tert-butyl phenol based dual COX-LOX inhibitors in colon cancer cells.
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Affiliation(s)
- Shibnath Ghatak
- Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Alok Vyas
- ISTRA Department of Chemistry, Abeda Inamdar Senior College, University of Pune, Pune 411001, India; Department of Bioinformatics and Computer Science, Dr. D.Y. Patil Biotechnology & Bioinformatics Institute, Dr. D.Y. Patil Vidyapeeth, Tathawade, Pune 411033, India
| | - Suniti Misra
- Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
| | - Paul O'Brien
- Hematology/Oncology Division, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Ajit Zambre
- Department of Chemistry, Bharati Vidyapeeth, Pune 411007, India
| | - Victor M Fresco
- Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Roger R Markwald
- Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - K Venkateshwara Swamy
- Department of Bioinformatics and Computer Science, Dr. D.Y. Patil Biotechnology & Bioinformatics Institute, Dr. D.Y. Patil Vidyapeeth, Tathawade, Pune 411033, India
| | - Zahra Afrasiabi
- Department of Life & Physical Sciences, Lincoln University, 820 Chestnut St., Jefferson City, MO 65101, USA
| | - Amitava Choudhury
- Department of Chemistry, Missouri S & T University (formerly University of Missouri-Rolla), Rolla, MO 65409, USA
| | - Madhukar Khetmalas
- Department of Bioinformatics and Computer Science, Dr. D.Y. Patil Biotechnology & Bioinformatics Institute, Dr. D.Y. Patil Vidyapeeth, Tathawade, Pune 411033, India
| | - Subhash Padhye
- ISTRA Department of Chemistry, Abeda Inamdar Senior College, University of Pune, Pune 411001, India.
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31
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Thomasz L, Oglio R, Rossich L, Villamar S, Perona M, Salvarredi L, Dagrosa A, Pisarev MA, Juvenal GJ. 6 Iodo-δ-lactone: a derivative of arachidonic acid with antitumor effects in HT-29 colon cancer cells. Prostaglandins Leukot Essent Fatty Acids 2013; 88:273-80. [PMID: 23375358 DOI: 10.1016/j.plefa.2013.01.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2012] [Revised: 12/26/2012] [Accepted: 01/04/2013] [Indexed: 01/21/2023]
Abstract
BACKGROUND IL-δ (5-hydroxy-6 iodo-8,11,14-eicosatrienoic delta lactone) an iodinated arachidonic acid (AA) derivative, is one of the iodolipids biosynthesized by the thyroid. Although IL-δ regulates several thyroid parameters such as cell proliferation and goiter growth it was found that this iodolipid inhibits the growth of other non thyroid cell lines. OBJECTIVES To study the effect of IL-δ on cell proliferation and apoptosis in the colon cancer cell line HT-29. RESULTS Treatment with IL-δ reduced cell viability in a concentration-dependent manner: 1μM 20%, 5μM 25%, 10μM 31%, 50μM 47% and caused a significant decrease of PCNA expression (25%). IL-δ had pro-apoptotic effects, evidenced by morphological features of programmed cell death such as pyknosis, karyorrhexis, cell shrinkage and cell blebbing observed by fluorescence microscopy, and an increase in caspase-3 activity and in Bax/Bcl-2 ratio (2.5 after 3h of treatment). Furthermore, IL-δ increased ROS production (30%) and lipid peroxidation levels (19%), suggesting that apoptosis could be a result of increased oxidative stress. A maximum increase in c-fos and c-jun protein expression in response to IL-δ was observed 1h after initiation of the treatment. IL-δ also induced a tumour growth delay of 70% compared to the control group in NIH nude mice implanted with HT-29 cells. CONCLUSION Our study shows that IL-δ inhibits cell growth and induces apoptosis in the colon cancer cell line, HT-29 and opens the possibility that IL-δ could be a potential useful chemotherapy agent.
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Affiliation(s)
- Lisa Thomasz
- Nuclear Biochemistry Division, Argentine National Atomic Energy Commission Buenos Aires 1429, Argentina
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Ganesh R, Marks DJB, Sales K, Winslet MC, Seifalian AM. Cyclooxygenase/lipoxygenase shunting lowers the anti-cancer effect of cyclooxygenase-2 inhibition in colorectal cancer cells. World J Surg Oncol 2012; 10:200. [PMID: 23013454 PMCID: PMC3527267 DOI: 10.1186/1477-7819-10-200] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2012] [Accepted: 09/10/2012] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Arachidonic acid metabolite, generated by cyclooxygenase (COX), is implicated in the colorectal cancer (CRC) pathogenesis. Inhibiting COX may therefore have anti-carcinogenic effects. Results from use of non-steroidal anti-inflammatory drugs inhibiting only COX have been conflicting. It has been postulated that this might result from the shunting of arachidonic acid metabolism to the 5-lipoxygenase (5-LOX) pathway. Cancer cell viability is promoted by 5-LOX through several mechanisms that are similar to those of cyclooxygenase-2 (COX-2). Expression of 5-LOX is upregulated in colorectal adenoma and cancer. The aim of this study was to investigate the shunting of arachidonic acid metabolism to the 5-LOX pathway by cyclooxygenase inhibition and to determine if this process antagonizes the anti-cancer effect in colorectal cancer cells. METHODS Three colorectal cancer cell lines (HCA7, HT-29 & LoVo) expressing 5-LOX and different levels of COX-2 expression were used. The effects of aspirin (a non-selective COX inhibitor) and rofecoxib (COX-2 selective) on prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) secretion were quantified by ELISA. Proliferation and viability were studied by quantifying double-stranded DNA (dsDNA) content and metabolic activity. Apoptosis was determined by annexin V and propidium iodide staining using confocal microscopy, and caspase-3/7 activity by fluorescent substrate assay. RESULTS COX inhibitors suppressed PGE2 production but enhanced LTB4 secretion in COX-2 expressing cell lines (P <0.001). The level of COX-2 expression in colorectal cancer cells did not significantly influence the anti-proliferative and pro-apoptotic effects of COX inhibitors due to the shunting mechanism. CONCLUSIONS This study provides evidence of shunting between COX and 5-LOX pathways in the presence of unilateral inhibition, and may explain the conflicting anti-carcinogenic effects reported with use of COX inhibitors.
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Affiliation(s)
- Radhakrishnan Ganesh
- Division of Surgery and Interventional Science, University College London, Rowland Hill Street, London NW3 2PF, UK.
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Kummer NT, Nowicki TS, Azzi JP, Reyes I, Iacob C, Xie S, Swati I, Darzynkiewicz Z, Gotlinger KH, Suslina N, Schantz S, Tiwari RK, Geliebter J. Arachidonate 5 lipoxygenase expression in papillary thyroid carcinoma promotes invasion via MMP-9 induction. J Cell Biochem 2012; 113:1998-2008. [PMID: 22253131 DOI: 10.1002/jcb.24069] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Arachidonate 5-lipoxygenase (ALOX5) expression and activity has been implicated in tumor pathogenesis, yet its role in papillary thyroid carcinoma (PTC) has not been characterized. ALOX5 protein and mRNA were upregulated in PTC compared to matched, normal thyroid tissue, and ALOX5 expression correlated with invasive tumor histopathology. Evidence suggests that PTC invasion is mediated through the induction of matrix metalloproteinases (MMPs) that can degrade and remodel the extracellular matrix (ECM). A correlation between MMP-9 and ALOX5 protein expression was established by immunohistochemical analysis of PTC and normal thyroid tissues using a tissue array. Transfection of ALOX5 into a PTC cell line (BCPAP) increased MMP-9 secretion and cell invasion across an ECM barrier. The ALOX5 product, 5(S)-hydroxyeicosatetraenoic acid also increased MMP-9 protein expression by BCPAP in a dose-dependent manner. Inhibitors of MMP-9 and ALOX5 reversed ALOX5-enhanced invasion. Here we describe a new role for ALOX5 as a mediator of invasion via MMP-9 induction; this ALOX5/MMP9 pathway represents a new avenue in the search for functional biomarkers and/or potential therapeutic targets for aggressive PTC.
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Affiliation(s)
- Nicolas T Kummer
- Department of Microbiology & Immunology, New York Medical College, Valhalla, New York 10595, USA
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Abstract
Polyunsaturated fatty acids (PUFA) play important roles in the normal physiology and in pathological states including inflammation and cancer. While much is known about the biosynthesis and biological activities of eicosanoids derived from ω6 PUFA, our understanding of the corresponding ω3 series lipid mediators is still rudimentary. The purpose of this review is not to offer a comprehensive summary of the literature on fatty acids in prostate cancer but rather to highlight some of the areas where key questions remain to be addressed. These include substrate preference and polymorphic variants of enzymes involved in the metabolism of PUFA, the relationship between de novo lipid synthesis and dietary lipid metabolism pathways, the contribution of cyclooxygenases and lipoxygenases as well as terminal synthases and prostanoid receptors in prostate cancer, and the potential role of PUFA in angiogenesis and cell surface receptor signaling.
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35
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Metabotyping of human colorectal cancer using two-dimensional gas chromatography mass spectrometry. Anal Bioanal Chem 2012; 403:483-93. [DOI: 10.1007/s00216-012-5870-5] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2011] [Revised: 02/11/2012] [Accepted: 02/12/2012] [Indexed: 02/07/2023]
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Chatterjee M, Das S, Roy K, Chatterjee M. Overexpression of 5-lipoxygenase and its relation with cell proliferation and angiogenesis in 7,12-dimethylbenz(α)anthracene-induced rat mammary carcinogenesis. Mol Carcinog 2011; 52:359-69. [DOI: 10.1002/mc.21858] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2011] [Revised: 11/03/2011] [Accepted: 11/22/2011] [Indexed: 11/06/2022]
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Zick SM, Turgeon DK, Vareed SK, Ruffin MT, Litzinger AJ, Wright BD, Alrawi S, Normolle DP, Djuric Z, Brenner DE. Phase II study of the effects of ginger root extract on eicosanoids in colon mucosa in people at normal risk for colorectal cancer. Cancer Prev Res (Phila) 2011; 4:1929-37. [PMID: 21990307 PMCID: PMC3208778 DOI: 10.1158/1940-6207.capr-11-0224] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Inhibitors of COX indicate that upregulation of inflammatory eicosanoids produced by COX, and in particular prostaglandin E(2) (PGE(2)), are early events in the development of colorectal cancer (CRC). Ginger has shown downregulation of COX in vitro and decreased incidence/multiplicity of adenomas in rats. This study was conducted to determine if 2.0 g/d of ginger could decrease the levels of PGE(2), 13-hydroxy-octadecadienoic acids, and 5-, 12-, and 15-hydroxyeicosatetraenoic acid (5-, 12-, and 15-HETE), in the colon mucosa of healthy volunteers. To investigate this aim, we randomized 30 subjects to 2.0 g/d ginger or placebo for 28 days. Flexible sigmoidoscopy at baseline and day 28 was used to obtain colon biopsies. A liquid chromatography mass spectrometry method was used to determine eicosanoid levels in the biopsies, and levels were expressed per protein or per free arachidonic acid. There were no significant differences in mean percent change between baseline and day 28 for any of the eicosanoids, when normalized to protein. There was a significant decrease in mean percent change in PGE(2) (P = 0.05) and 5-HETE (P = 0.04), and a trend toward significant decreases in 12-HETE (P = 0.09) and 15-HETE (P = 0.06) normalized to free arachidonic acid. There was no difference between the groups in terms of total adverse events P = 0.55). On the basis of these results, it seems that ginger has the potential to decrease eicosanoid levels, perhaps by inhibiting their synthesis from arachidonic acid. Ginger also seemed to be tolerable and safe. Further investigation in people at high risk for CRC seems warranted.
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Affiliation(s)
- Suzanna M Zick
- Department of Family Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA.
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Mohammed A, Janakiram NB, Li Q, Choi CI, Zhang Y, Steele VE, Rao CV. Chemoprevention of colon and small intestinal tumorigenesis in APC(Min/+) mice by licofelone, a novel dual 5-LOX/COX inhibitor: potential implications for human colon cancer prevention. Cancer Prev Res (Phila) 2011; 4:2015-26. [PMID: 21885812 DOI: 10.1158/1940-6207.capr-11-0233] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Preclinical and clinical studies suggest that 5-lipoxygenase (5-LOX), such as COX-2, is a potential target for colon cancer inhibition and, in part, contributes to cardiovascular side effects associated with COX-2 inhibitors. Experiments were designed to assess the chemopreventive effects of a novel dual 5-LOX/COX inhibitor, licofelone {[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl] acetic acid}, in APC(Min/+) mouse intestinal tumorigenesis. Six-week-old male and female APC(Min/+) mice (n = 10 per group) were fed with control American Institute of Nutrition-76A diet or diets containing 150 or 300 ppm licofelone for 14 weeks (∼100 days), and intestinal tumors were evaluated for tumor multiplicity and size. Licofelone significantly inhibited total intestinal tumor multiplicity and size in a dose-dependent manner (P < 0.0001; mean tumors for 0, 150, and 300 ppm: 48.8, 17, and 8, respectively, in male mice; and 34.3, 8.8, and 5.5, respectively, in female mice). Licofelone at high dose showed more than 83% (P < 0.0001) tumor inhibition in both genders of mice. One hundred and fifty and 300 ppm licofelone resulted in 86% to 97% inhibition of polyps having size greater than 2 mm. One hundred and fifty and 300 ppm licofelone caused more than 72% and 100% inhibition of colonic tumors, respectively. Importantly, in mice fed with licofelone, tumors showed significantly reduced proliferating cell nuclear antigen expression (70%, P < 0.0001), increased terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells (75%, P < 0.0001), and there was dose-dependent suppression of serum triglycerides (71%-83%, P < 0.0001), decreased inflammatory cytokines; and decreased COX and 5-LOX activities (57%-64%, P < 0.0001). Also, compared with 300 ppm celecoxib, 300 ppm licofelone provided better efficacy in suppressing tumor growth. These observations show that a novel dual 5-LOX/COX inhibitor dramatically suppresses small intestinal and colonic tumor formation in APC(Min/+) mice.
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Affiliation(s)
- Altaf Mohammed
- Department of Medicine, Hem-Onc Section, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
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39
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Katsori AM, Chatzopoulou M, Dimas K, Kontogiorgis C, Patsilinakos A, Trangas T, Hadjipavlou-Litina D. Curcumin analogues as possible anti-proliferative & anti-inflammatory agents. Eur J Med Chem 2011; 46:2722-35. [PMID: 21514701 DOI: 10.1016/j.ejmech.2011.03.060] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2011] [Revised: 03/21/2011] [Accepted: 03/29/2011] [Indexed: 01/25/2023]
Abstract
A series of novel curcumin analogues has been designed, synthesized and tested in vitro/in vivo as potential multi-target agents. Their anti-proliferative and anti-inflammatory activities were studied. Compounds 1b and 2b were stronger inhibitors of soybean lipoxygenase (LOX) than curcumin. Analogue 1b was also the most potent aldose reductase (ALR2) inhibitor. Two compounds, (1a and 1f) exhibited in vivo anti-inflammatory activity comparable to that of indomethacin, whereas derivative 1i exhibited even higher activity. The derivatives were also tested for their anti-proliferative activity using three different human cancer cell lines. Compounds 1a, 1b, 1d and 2b exhibited significant growth inhibitory activity as compared to curcumin, against all three cancer cell lines. Lipophilicity was determined as R(M) values using RPTLC and theoretically. The results are discussed in terms of the structural characteristics of the compounds. Docking simulations were performed on LOX and ALR2 inhibitor 1b and curcumin. Compound 1b is well fitted in the active site of ALR2, binding to the ALR2 enzyme in a similar way to curcumin. Allosteric interactions may govern the LOX-inhibitor binding.
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Affiliation(s)
- A-M Katsori
- Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece
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40
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Mal M, Koh PK, Cheah PY, Chan ECY. Ultra-pressure liquid chromatography/tandem mass spectrometry targeted profiling of arachidonic acid and eicosanoids in human colorectal cancer. RAPID COMMUNICATIONS IN MASS SPECTROMETRY : RCM 2011; 25:755-764. [PMID: 21337637 DOI: 10.1002/rcm.4926] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/30/2023]
Abstract
Cumulative evidence shows that eicosanoids such as prostaglandins, leukotrienes, thromboxanes and hydroxy eicosatetraenoic acids play an important role in associating inflammation with human colorectal cancer (CRC). In this study an ultra-pressure liquid chromatography/tandem mass spectrometry (UPLC/MS/MS) method was developed and validated for the targeted profiling of eight relevant eicosanoids and the major metabolic precursor, arachidonic acid (AA), in human colon. Multiple reaction monitoring (MRM) experiments were performed in negative electrospray ionization mode. The metabolites were separated using a C(18) column consisting of 1.7 µm ethylene-bridged hybrid particles (100 × 2.1 mm i.d.) and gradient elution (50 to 95% of solvent B) with a mobile phase comprising water (0.1% formic acid) [solvent A] and acetonitrile (0.1% formic acid) [solvent B] at a flow rate of 0.4 mL/min. The analysis time for each sample was 5.5 min. Our UPLC/MS/MS method demonstrated satisfactory validation results in terms of selectivity, sensitivity, matrix effect, linearity, extraction efficiency, intra- and inter-day precision, accuracy and autosampler stability. The method was applied for the clinical profiling of matched pairs of cancerous and normal colon mucosae obtained from eight colorectal cancer patients. Endogenous levels of AA and selected eicosanoids such as prostaglandin E(2) (PGE(2)), prostacyclin (PGI(2)) [assayed as its stable hydrolytic product 6-keto-prostaglandin(1α) (6-k PGF(1α))] and 12-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid (12-HETE) were found to be significantly different (p <0.05; paired t-test) between cancerous and normal mucosae.
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Affiliation(s)
- Mainak Mal
- Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore
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41
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Affiliation(s)
- Rajeshwar P Verma
- Department of Chemistry, Pomona College, 645 North College Avenue, Claremont, California 91711, USA.
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Matsuyama T, Ishikawa T, Mogushi K, Yoshida T, Iida S, Uetake H, Mizushima H, Tanaka H, Sugihara K. MUC12 mRNA expression is an independent marker of prognosis in stage II and stage III colorectal cancer. Int J Cancer 2010; 127:2292-9. [PMID: 20162577 DOI: 10.1002/ijc.25256] [Citation(s) in RCA: 78] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Distant metastasis is the major cause of death in colorectal cancer (CRC) patients. To identify genes influencing the prognosis of patients with CRC, we compared gene expression in primary tumors with and without distant metastasis using an oligonucleotide microarray. We also examined the expression of the candidate gene in 100 CRC patients by quantitative real-time reverse transcription PCR and studied the relationship between its expression and the prognosis of patients with CRC. As a result, we identified MUC12 as a candidate gene involved in metastasis processes by microarray analysis. Quantitative real-time reverse transcription PCR showed that MUC12 expression was significantly lower in cancer tissues than in adjacent normal tissues (p < 0.001). In Stages II and III CRC, patients with low expression showed worse disease-free survival (p = 0.020). Multivariate analysis disclosed that MUC12 expression status was an independent prognostic factor in Stages II and III CRC (relative risk, 8.236; 95% confidence interval, 1.702-39.849 p = 0.009). Our study revealed the prognostic value of MUC12 expression in CRC patients. Moreover, our result suggests MUC12 expression is a possible candidate gene for assessing postoperative adjuvant therapy for CRC patients.
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Affiliation(s)
- Takatoshi Matsuyama
- Department of Surgical Oncology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
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Goodman LA, Jarrett CL, Krunkosky TM, Budsberg SC, Northrup NC, Saba CF, LeRoy BE. 5-Lipoxygenase expression in benign and malignant canine prostate tissues*. Vet Comp Oncol 2010; 9:149-57. [DOI: 10.1111/j.1476-5829.2010.00245.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Wasilewicz MP, Kołodziej B, Bojułko T, Kaczmarczyk M, Sulzyc-Bielicka V, Bielicki D, Ciepiela K. Overexpression of 5-lipoxygenase in sporadic colonic adenomas and a possible new aspect of colon carcinogenesis. Int J Colorectal Dis 2010; 25:1079-85. [PMID: 20549218 PMCID: PMC2912725 DOI: 10.1007/s00384-010-0980-z] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/27/2010] [Indexed: 02/07/2023]
Abstract
PURPOSE We aimed to study the intracellular expression of 5-lipoxygenase (5-LOX), the primary competitor with cyclooxygenase-2 in arachidonic acid metabolism, as inflammatory enzymes may be involved in blocking apoptosis and promoting cancer growth by changing arachidonic acid metabolism within cells. Our purpose was to investigate the possible connection between 5-LOX expression and colon carcinogenesis by characterizing 5-LOX expression in histologically different colonic adenomas, determining the relationship between high expression of 5-LOX and various conventional clinicopathological features of adenomas, and finally characterizing the histological localization of cells with 5-LOX overexpression. METHODS A total of 111 patients were examined and 120 histologically different colonic adenomas analyzed (including four cases of intramucosal adenocarcinoma in a polyp). Immunohistochemical staining with polyclonal anti-5-LOX antibodies was performed. RESULTS There was a significant correlation between high 5-LOX expression and patient age, increased polyp size, high grade of intraepithelial neoplasia, villous and tubulovillous adenoma, and histological epithelial localization. CONCLUSIONS We observed a strong positive correlation between 5-LOX overexpression and the appearance of typical high-risk factors for malignant transformation in adenomatous polyps. The results support the role of 5-LOX in early stages of colon carcinogenesis.
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Affiliation(s)
- Michał P Wasilewicz
- Department of Gastroenterology, Pomeranian Medical University, Szczecin, Poland.
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45
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Sahebkar A, Iranshahi M. Cancer Chemoprevention by 7-Prenyloxycoumarins: A Role for 5-Lipoxygenase Inhibition? Integr Cancer Ther 2010; 9:259-60. [DOI: 10.1177/1534735410378662] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Affiliation(s)
- Amirhossein Sahebkar
- Biotechnology Research Center and School of Pharmacy, Mashhad University of Medical Sciences (MUMS), Mashhad, Iran, Cardiovascular Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences (MUMS), Mashhad, Iran,
| | - Mehrdad Iranshahi
- Biotechnology Research Center and School of Pharmacy, Mashhad University of Medical Sciences (MUMS), Mashhad, Iran
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Simopoulos AP. Genetic variants in the metabolism of omega-6 and omega-3 fatty acids: their role in the determination of nutritional requirements and chronic disease risk. Exp Biol Med (Maywood) 2010; 235:785-95. [PMID: 20558833 DOI: 10.1258/ebm.2010.009298] [Citation(s) in RCA: 152] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
The tissue composition of polyunsaturated fatty acids is important to health and depends on both dietary intake and metabolism controlled by genetic polymorphisms that should be taken into consideration in the determination of nutritional requirements. Therefore at the same dietary intake of linoleic acid (LA) and alpha-linolenic acid (ALA), their respective health effects may differ due to genetic differences in metabolism. Delta-5 and delta-6 desaturases, FADS1 and FADS2, respectively, influence the serum, plasma and membrane phospholipid levels of LA, ALA and long-chain polyunsaturated fatty acids during pregnancy, lactation, and may influence an infant's IQ, atopy and coronary heart disease (CHD) risk. At low intakes of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), polymorphisms at the 5-lipoxygenase (5-LO) level increase the risk for CHD whereas polymorphisms at cyclooxgenase-2 increase the risk for prostate cancer. At high intakes of LA the risk for breast cancer increases. EPA and DHA influence gene expression. In future, intervention studies on the biological effects of LA, ALA and LC-PUFAs, and the effects of genetic variants in FADS1 and FADS2, 5-LO and cyclooxygenase-2 should be taken into consideration both in the determination of nutritional requirements and chronic disease risk. Furthermore, genome-wide association studies need to include environmental exposures and include diet in the interaction between genetic variation and disease association.
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Affiliation(s)
- Artemis P Simopoulos
- The Center for Genetics, Nutrition and Health, 2001 S Street NW, Washington, DC 20009, USA.
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Decrease in uptake of arachidonic acid by indomethacin in LS174T human colon cancer cells; a novel cyclooxygenase-2-inhibition-independent effect. Arch Biochem Biophys 2010; 494:78-85. [DOI: 10.1016/j.abb.2009.11.025] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2009] [Revised: 11/11/2009] [Accepted: 11/18/2009] [Indexed: 11/18/2022]
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Kunnumakkara AB, Guha S, Aggarwal BB. Curcumin and colorectal cancer: Add spice to your life. CURRENT COLORECTAL CANCER REPORTS 2009; 5:5-14. [DOI: 10.1007/s11888-009-0002-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
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50
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Melstrom LG, Bentrem DJ, Salabat MR, Kennedy TJ, Ding XZ, Strouch M, Rao SM, Witt RC, Ternent CA, Talamonti MS, Bell RH, Adrian TA. Overexpression of 5-lipoxygenase in colon polyps and cancer and the effect of 5-LOX inhibitors in vitro and in a murine model. Clin Cancer Res 2008; 14:6525-30. [PMID: 18927292 DOI: 10.1158/1078-0432.ccr-07-4631] [Citation(s) in RCA: 116] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE Arachidonic acid metabolism via the cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) pathways modulates cell growth and apoptosis. Many studies have examined the effects of COX inhibitors on human colorectal cancer, but the role of 5-LOX in colonic cancer development has not been well studied. The purpose of this study was to evaluate the expression of 5-LOX in colonic polyps and cancer and the effect of 5-LOX inhibition on colon cancer cell proliferation. EXPERIMENTAL DESIGN Colonic polyps, cancer, and normal mucosa were evaluated for 5-LOX expression by immunohistochemistry. Reverse transcription-PCR was used to establish 5-LOX expression in colon cancer cells. Thymidine incorporation and cell counts were used to determine the effect of the nonspecific LOX inhibitor Nordihydroguaiaretic Acid and the 5-LOX inhibitor Rev5901 on DNA synthesis. A heterotopic xenograft model in athymic mice using HT29 and LoVo human colon cancer cells was used to evaluate the effect of the 5-LOX inhibitor zileuton on tumor growth. RESULTS 5-LOX is overexpressed in adenomatous polyps and cancer compared with that of normal colonic mucosa. LOX inhibition and 5-LOX inhibition decreased DNA synthesis in a concentration- and time-dependent manner in the Lovo cell line (P < 0.05). Inhibition of 5-LOX in an in vivo colon cancer xenograft model inhibited tumor growth compared with that of controls (P < 0.05). CONCLUSIONS This study showed that 5-LOX is up-regulated in adenomatous colon polyps and cancer compared with normal colonic mucosa. The blockade of 5-LOX inhibits colon cancer cell proliferation both in vitro and in vivo and may prove a beneficial chemopreventive therapy in colon cancer.
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Affiliation(s)
- Laleh G Melstrom
- Department of Surgery and Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
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